Download bioavailability enhancdement of poorly soluble drugs by smedds

Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
98
Available online at http://jddtonline.info
REVIEW ARTICLE
BIOAVAILABILITY ENHANCDEMENT OF POORLY SOLUBLE DRUGS BY SMEDDS: A
REVIEW
Jaiswal Parul*, Aggarwal Geeta, Harikumar SL, Kaur Amanpreet
Rayat and Bahra Institute of Phamacy, Sahauran, Kharar, District Mohali, Punjab, India-140104
*Corresponding Author’s E-mail: [email protected], Contact No: +91-9872711223
Received 10 Dec 2012; Review Completed 01 Jan 2013; Accepted 01 Jan 2013, Available online 15 Jan 2013
ABSTRACT
Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way
investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic
bioavailability, which mainly results from poor aqueous solubility, thereby pretense problems in their formulation. More than
40% of potential drug products suffer from poor water solubility. For the therapeutic delivery of lipophilic active moieties
(BCS class II drugs), lipid based formulations are inviting increasing attention. Currently a number of technologies are
available to deal with the poor solubility, dissolution rate and bioavailability of insoluble drugs such as micronization, solid
dispersions or cyclodextrin complex formation and different technologies of drug delivery systems. One of the promising
techniques is Self‐Micro Emulsifying Drug Delivery Systems (SMEDDS). Self emulsifying drug delivery system has gained
more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug
absorption, selective targeting of drug(s) toward specific absorption window in GIT, and protection of drug(s) from the
unreceptive environment in gut. This article gives a complete overview of SMEDDS as a promising approach to effectively
deal with the problem of poorly soluble molecules.
Keywords: SMEDDS, surfactant, oil, co-surfactant, bioavailability
INTRODUCTION
The oral delivery of lipophilic drugs presents a major
challenge because of the low aqueous solubility. Lipidbased formulations have been shown to enhance the
bioavailability of drugs administered orally1, 2, 3, 4. Wide
availability of lipidic excipients with specific
characteristics offers flexibility of application with respect
to improving the bioavailability of poorly water-soluble
drugs and manipulating their release profiles5.
Selfmicroemulsifying drug delivery system(SMEDDS) are
defined as isotropic mixtures of natural or synthetic oils,
solid or liquid surfactants, or alternatively, one or more
hydrophilic solvents and co-solvents/surfactants that have
a unique ability of forming fine oil-in-water (o/w) micro
emulsions upon mild agitation followed by dilution in
aqueous media, such as GI fluids6.
The self emulsification process is specific to the particular
pair of oil and surfactant, surfactant concentration,
oil/surfactant ratio, and the temperature at which
self‐emulsification occurs7, 8, 9. After self dispersion, the
drug is rapidly distributed throughout the gastrointestinal
tract as fine droplets. The large surface area enhances the
dissolution. The emulsion globules are further solubilized
in the gastrointestinal tract by bile fluids. The presence of
surfactant causes enhanced absorption due to membrane
induced permeation changes. The droplets formed are
either positively charged or negatively charged. As the
mucosal lining is negatively charged it was observed that
positively charged particles penetrated deeper into the
ileum10. A cationic emulsion has greater bioavailability
than an anionic emulsion11, 12. Self‐Emulsifying Drug
Delivery Systems (SEDDS) formed using surfactants of
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HLB <12 and Self‐Micro Emulsifying Drug Delivery
Systems (SMEDDS) formed with surfactants of HLB > 12.
Both SEDDS and SMEDDS are stable preparations and
improve the dissolution of the drug due to increased
surface area on dispersion. The emulsified form itself is
readily absorbable which ensures a rapid transport of
poorly soluble drugs into the blood. Many researchers have
reported applications of SEDDS for delivering and
targeting lipophilic drugs e.g., coenzyme Q1013, vitamin
E14, halofantrine15 and cyclosporine A16. Upon per oral
administration, these systems form fine emulsions (or
micro-emulsions) in gastro-intestinal tract (GIT) with mild
agitation provided by gastric mobility. Khoo et al (1988)
demonstrated enhanced drug absorption when using long
chain triglycerides (LCT) compared with medium chain
triglycerides (MCT) in the SMEDDS formulations15.
These findings are attributed to maximal stimulation of
lymphatic transport by the LCT. Studies indicated that the
rate of intestinal absorption of N-LCT was similar to that
of the other Pharmacopoeial vegetable oils such as,
sunflower, sesame and groundnut oil17; suggesting that the
N-LCT is acceptable for human consumption and
pharmaceutical applications. The N-LCT offers many
other advantages such as, easy availability in large
quantities from natural source, toxicologically safe,
completely biocompatible and cost effective replacement
for commercial triglycerides and modified oils.
NEED OF SMEDDS
Oral delivery of poorly water-soluble compounds is to predissolve the compound in a suitable solvent and fill the
formulation into capsules. The main benefit of this
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Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
approach is that pre-dissolving the compound overcomes
the initial rate limiting step of particulate dissolution in the
aqueous environment within the GI tract. However, a
potential problem is that the drug may precipitate out of
solution when the formulation disperses in the GI tract,
particularly if a hydrophilic solvent is used (e.g.
polyethylene glycol). If the drug can be dissolved in a lipid
vehicle there is less potential for precipitation on dilution
in the GI tract, as partitioning kinetics will favor the drug
remaining in the lipid droplets. Another strategy for poorly
soluble drugs is to formulate in a solid solution using a
water-soluble polymer to aid solubility of the drug
compound. For example, polyvinylpyrrolidone (PVP) and
polyethylene glycol (PEG 6000) have been used for
preparing solid solutions with poorly soluble drugs. One
potential problem with this type of formulation is that the
drug may favor a more thermodynamically stable state,
which can result in the compound crystallizing in the
polymer matrix. Therefore the physical stability of such
formulations needs to be assessed using techniques such as
differential
scanning
calorimetry
or
X-ray
crystallography18. Self-micro emulsifying drug delivery
system is a novel approach and is being extensively used
to enhance the solubility and bioavailability of poorly
water soluble drugs. In addition to this, the formulated
SMEDDS will also prevent the drug from hostile gastric
environment which will further help in better systemic
absorption.
ADVANTAGES OF SMEDDS

Improvement in oral bioavailability
The ability of SMEDDS to present the drug to GIT in
solubilised and micro emulsified form (globule size
between 1-100 nm) and subsequent increase in specific
surface area enable more efficient drug transport through
the intestinal aqueous boundary layer and through the
absorptive brush border membrane leading to improved
bioavailability. E.g. In case of halofantrine approximately
6-8 fold increase in bioavailability of drug was reported in
comparison to tablet formulation 15.

Ease of manufacture and scale-up
SMEDDS require very simple and economical
manufacturing facilities like simple mixer with agitator
and volumetric liquid filling equipment for large-scale
manufacturing. This explains the interest of industry in the
SMEDDS.
 Reduction in inter-subject
variability and food effects
and
intra-subject
There are several drugs which show large inter-subject and
intra-subject variation in absorption leading to decreased
performance of drug and patient non-compliance. Food is a
major factor affecting the therapeutic performance of the
drug in the body. SMEDDS are a boon for such drugs.
Several research papers specifying that, the performance of
SMEDDS is independent of food and, SMEDDS offer
reproducibility of plasma profile are available18.

Ability to deliver peptides that are prone to
enzymatic hydrolysis in GIT
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99
SMEDDS are superior as compared to the other drug
delivery systems due to their ability to deliver
macromolecules like peptides, hormones, enzyme
substrates and inhibitors and their ability to offer
protection from enzymatic hydrolysis. The intestinal
hydrolysis of prodrug by cholinesterase can be protected if
Polysorbate 20 is emulsifier in micro emulsion
formulation19. These systems are formed spontaneously
without aid of energy or heating thus suitable for
thermolabile drugs such as peptides20.

No influence of lipid digestion process
Unlike the other lipid-based drug delivery systems, the
performance of SMEDDS is not influenced by the
lipolysis, emulsification by the bile salts, action of
pancreatic lipases and mixed micelle formation.

Increased drug loading capacity
As the solubility of poorly water soluble drugs with
intermediate partition coefficient (2<log P>4) are typically
low in natural lipids and much greater in amphilic
surfactants, co surfactants and co-solvents.
 In SMEDDS, the lipid matrix interacts readily with
water, forming a fine particulate oilin-water (o/w) emulsion. The emulsion droplets will
deliver the drug to the gastrointestinal mucosa in the
dissolved state readily accessible for absorption. Therefore
increase in AUC i.e. bioavailability and C max is observed
with many drugs when presented in SMEDDS21.

Fine oil droplets empty rapidly from the stomach and
promote wide distribution of drug throughout the
intestinal tract and thereby minimizing irritation
frequently encountered with extended contact of drugs
and gut wall22.

When polymer is incorporated in composition of
SMEDDS it gives prolonged release of
medicament23.
 SMEDDS present drugs in a small droplet size and
well-proportioned distribution and increase the dissolution
and permeability. Furthermore, because drugs can be
loaded in the inner phase and delivered to the lymphatic
system, can bypass first pass metabolism. Thus SMEDDS
reduce the presystemic clearance in the GI mucosa and
hepatic first-pass metabolism.

Selective targeting of drug(s) toward
absorption window in GIT21.

Protection of drug(s) from the hostile environment in
gut22.

Protective of sensitive drug substances.

Liquid or solid dosage forms
specific
ADVANTAGES OF SMEDDS OVER EMULSION

SMEDDS not only offer the same advantages of
emulsions of facilitating the solubility of
hydrophobic drugs, but also overcomes the drawback
of the layering of emulsions after sitting for a long
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Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
time. It can be easily stored since it belongs to a
thermodynamics stable system.

formulation of progesterone in SMEDDS has been
prepared by the process of extrusion spheronization to
provide a good in vitro drug release (100% within 30
min, T50% at 13 min). The same dose of progesterone
(16 mg) in pellets and in the SEDDS liquid
formulation resulted in similar AUC, C max and T
max values27. Applications of SMEEDS are enlisted
in Table 1.
Microemulsions formed by the SMEDDS exhibit good
thermodynamics stability and
optical transparency. Droplets of microemulsion
formed by the SMEDDS generally ranges between 2
and 100 nm. Since the particle size is small, the total
surface area for absorption and dispersion is
significantly larger than that of solid dosage form and
it can easily penetrate the gastrointestinal tract and be
absorbed. The bioavailability of the drug is therefore
improved.

SMEDDS offer numerous delivery options like can be
filled in hard gelatin capsules or soft gelatin capsules
or can be formulated into tablets whereas emulsions
can only be given as oral solutions.

Emulsion cannot be autoclaved as they have phase
inversion temperature, while SMEDDS can be
autoclaved24.
DISADVANTAGES OF SMEDDS25

Lack of good predicative in vitro models for
assessment of the formulations.

This in vitro model needs further development and
validation before its strength can be evaluated.
 Further development will be based on in vitro - in vivo
correlations and therefore different prototype lipid
based formulations needs to be developed and tested
in vivo in a suitable animal model.

Another is chemical instabilities of drugs and high
surfactant
concentrations
in
formulations
(approximately 30-60%) which irritate GIT.

Moreover, volatile co solvents in the conventional
self-microemulsifying formulations are known to
migrate into the shells of soft or hard gelatin capsules,
resulting in the precipitation of the lipophilic drugs.

The precipitation tendency of the drug on dilution may
be higher due to the dilution effect of the hydrophilic
solvent.
APPLICATIONS OF SMEDDS

SUPERSATURABLE SMEDDS (S-SMEDDS): SSMEDDS formulations have been designed and
developed to reduce the surfactant side effects and
achieve rapid absorption of poorly soluble drugs26.

SOLID SMEDDS: SMEDDS are normally prepared
as liquid dosage forms that can be administrated in
soft gelatin capsules, which have some disadvantages
especially in the manufacturing process. An
alternative method is the incorporation of liquid self
emulsifying ingredients into a powder in order to
create a solid dosage form (tablets, capsules). A pellet
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100
FORMULATION COMPONENTS OF SMEDDS:










Drug
Oil
Surfactant
Co-surfactant
Co-solvent
Consistency Builder
Enzyme Inhibitors
Adsorbents/solidifying agents
Polymers
Other Components
Oils: The oil represents one of the most important
excipients in the SMEDDS formulation not only because it
can solubilize the required dose of the lipophilic drug or
facilitate self emulsification but also and mainly because it
can increase the fraction of lipophilic drug transported via
the intestinal lymphatic system, thereby increasing
absorption from the GI tract depending on the molecular
nature of the triglyceride29. Both long and medium chain
triglyceride (LCT and MCT) oils with different degrees of
saturation have been used for the design of selfemulsifying formulations. Furthermore, edible oils which
could represent the logical and preferred lipid excipient
choice for the development of SMEDDS are not frequently
selected due to their poor ability to dissolve large amounts
of lipophilic drugs. Modified or hydrolyzed vegetable oils
have been widely used since these excipients form good
emulsification systems with a large number of surfactants
approved for oral administration and exhibit better drug
solubility properties. They offer formulative and
physiological advantages and their degradation products
resemble the natural end products of intestinal digestion.
Novel semisynthetic medium chain derivatives, which can
be defined as amphiphilic compounds with surfactant
properties, are progressively and effectively replacing the
regular medium chain triglyceride oils in the SMEDDS25.
This is in accordance with findings of Deckelbaum (1990)
showing that MCT is more soluble and have a higher
mobility in the lipid/water interfaces than LCT associated
with a more rapid hydrolysis of MCT. Almond oil, Canola
oil, Coconut oil, Coconut oil, Corn oil, Cottonseed oil,
Olive oil, Peanut oil, Safflower oil, Sesame oil, Shark liver
oil, Soyabean oil, Wheat germ oil etc are the commercially
available triglycerides30.
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Table: 1 Applications of SMEDDS reported in literature28
Type Of
Delivery
System
SMEDDS
DRUG
OIL
Surfactant
Co-solvent /
Cosurfactant
SIGNIFICANCE
Atorvastatin
Labrafil, Estol
and Isopropyl
myristate
Cremophore El,
Cremophor RH
40
Improves solubility bioavailability and
permeability via the mucous membrane. Oral
bioavailability increased nearly 1.5 times.
SMEDDS
Simvastatin
Caproyl 90
Cremophore EL
Propylene
glycol, PEG
400 and
Transcutol
Carbitol
SMEDDS
Seocalcitol
Viscoleo
(MCT),
Sesame oil
(LCT)
Cremophore
RH40
Akoline
SEDDS
Ontazolast
Silmyrin
Solid,Polyglycolyzed mono-di
and triglycerides,
Tween 80
Tween 80
-
SMEDDS
mixture of
mono-and
diglyceri-des
of oleic acid
Ethyl linoleate
Self
Emulsifying
Pellets
Methyl and
propyl
parabens
Tween 80
-
SEDDS
Ketoprufen
Mono &
diglycerides of
capric and
caprylic acids
Captex 200
Tween 80
Capmul MCM
SEDDS
Crvedilol
Labrasol
Transcutol P
SEDDS
Itraconazole
Tocopherol
acetate
Labrafil M
1944CS
Pluronic L64
Transcutol
Greatly enhanced bioavailability without the
influence of food.
SNEDDS
Cefpodoxime proxetil
(CFP)
Capryol 90
Cremophor
EL, Solutol
HS
Akoline
High dose of CFP (130 mg) exhibited rapid
release independent of pH of dissolution
media.
Surfactant: Surfactant molecules may be classified based
on the nature of the hydrophilic group within the molecule.
The four main groups of surfactants are defined as follows:
Anionic Surfactants, where the hydrophilic group carries
a negative charge such as carboxyl (RCOO-),sulphonate
(RSO3-) or sulphate (ROSO3-). Examples: Potassium
laurate, sodium lauryl sulphate.
Cationic surfactants, where the hydrophilic group carries
a positive charge. Example: quaternary ammonium halide.
Ampholytic surfactants (also called zwitterionic
surfactants) contain both a negative and a positive charge.
Example: sulfobetaines.
Nonionic surfactants, where the hydrophilic group carries
no charge but derives its water solubility from highly polar
groups such as hydroxyl or polyoxyethylene
(OCH2CH2O). Examples: Sorbitan esters (Spans),
polysorbates (Tweens).
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Ethyl alcohol
Release rate was higher than conventional
tablets. The oral bioavailability of SMEDDS is
about 1.5-fold higher than conventional
tablets.
No improvement in bioavailability. After three
months of storage at accelerated conditions
(40°C/75% RH), a decrease in concentration
of 10-11% was found. Simple lipid solutions
are better choice compared with the developed
SMEDDS due to a slightly higher
biovailability and better chemical stability.
Enhanced bioavailability by 7.5 drug content.
Release was limited, incomplete and typical of
sustained characteristics. Relative
bioavailability dramatically enhanced in an
average of 1.88 and 48.82 fold that of
silymarin PEG 400 solution and suspension
respectively.
Improved rate of drug release from the pellets.
By applying a water insoluble polymer
containing a water soluble plastisizer it
reduces the rate of drug release
Silicon dioxide was used as gelling agent. As
the concentration of silicon dioxide increases,
it causes an increase in the droplet size and
slows the drug diffusion.
Improves the oral bioavailability of upto 413%
Nonionic surfactants with high hydrophilic lipophilic
balance (HLB) values are used in formulation of
SMEDDS. The usual surfactant strength ranges between
30-60% w/w of the formulation in order to form a stable
SMEDDS. Surfactants having a high HLB and
hydrophilicity assist the immediate formation of o/w
droplets and/or rapid spreading of the formulation in the
aqueous media. Surfactants are amphiphilic in nature and
they can dissolve or solubilize relatively high amount of
hydrophobic drug compounds31. Safety is a major
determining factor in choosing a surfactant. Emulsifiers of
natural origin are preferred since they are considered to be
safer than the synthetic surfactants29. However, these
surfactants have a limited self emulsification capacity.
Non-ionic surfactants are less toxic than ionic surfactants
but they may lead to reversible changes in the permeability
of the intestinal lumen 32. Large amounts of surfactants may
cause GI irritation. There is a relationship between the
droplet size and the concentration of the surfactant being
used. In some cases, increasing the surfactant
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concentration could lead to droplets with smaller mean
droplet size, this could be explained by the stabilization of
the oil droplets as a result of the localization of the
surfactant molecules at the oil-water interface33. On the
other hand, in some cases the mean droplet size may
increase with increasing surfactant concentrations34. This
phenomenon could be attributed to the interfacial
disruption elicited by enhanced water penetration into the
oil droplets mediated by the increased surfactant
concentration and leading to ejection of oil droplets into
the aqueous phase35. The surfactants used in these
formulations are known to improve the bioavailability by
various mechanisms including: improved drug dissolution,
increased intestinal epithelial permeability, increased tight
junction permeability and decreased/inhibited pglycoprotein drug efflux.
Co-surfactants: Generally co-surfactant of HLB value 1014 is used with surfactant together to decrease the
interfacial tension to a very small even transient negative
value. At this value the interface would expand to form
fine dispersed droplets, and subsequently adsorb more
surfactant until their bulk condition is depleted enough to
make interfacial tension positive again. This process is
known as spontaneous emulsification forms the
microemulsion. The selection of co-surfactant and
surfactant is crucial not only to form the formation of
microemulsion,
but
also to solubilization
in
microemulsions. Other variables such as the chemical
nature of oil, salinity and temperature are also expected to
influence the curvature of the interfacial film. Organic
solvents like ethanol, propylene glycol, polyethylene
glycol suitable for oral administration may help to dissolve
large amounts of either the hydrophilic surfactant or the
drug in the lipid base and can act as cosurfactant in the
microemulsion systems. Literature has been described
alcohol and propylene glycol free self emulsifying
microemulsions21, 36. The drugs in the alcohol free
formulations may exhibit limited solubility. Hydrophilic
co-surfactants are preferably alcohols of intermediate
chain length such as hexanol, pentanol and octanol, which
are known to reduce the oil/water interface and allow the
spontaneous formulation of microemulsion. Examples of
various surfactants, co-surfactants and cosolvents used in
Commercial formulations are enlisted in Table 2.
Co-solvents: Organic solvents and additional compounds
suitable for oral administration are used in SMEDDS to
enhance the solubility of therapeutic agent or triglyceride
in the composition37. Examples;

Alcohols and Polyols: Such as ethanol, isopropranol,
butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol,
pentaerythritol, sorbitol, mannitol,
transcutol,
dimethyl isosorbide, propylene glycol, polypropylene
glycol, hydroxyprpyl methyl cellulose and other
cellulosic polymers, cyclodextrins and its derivatives.

Esters of propylene glycols having average molecular
weight of about 200 to 6000 such as tetrahydrofuryl
alcohol, PEG ether (glycofural) or methoxy PEG.
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102

Amides such as 2-pyrrolidone, 2-piperidone,
caprolactam,
N-alkylpyrrolidone,
Nhydroxyalkylepyrrolidone,
N-alkylpiperidone,
Nalkylcaprolactam, dimethylacetamide an polyvinyl
pyrrolidone.

Esters, such as ethyl propionate, tributyl citrate, acetyl
triethyle citrate, acetyl tributyl citrate, ethylene oleate,
ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate, caprolactone, -valerolactone, -butyrolactone.
Consistency builder: Tragacanth, cetyl alcohol, stearic
acid or beeswax can be added to alter the consistency of
the emulsion23.
Enzyme inhibitors: If the therapeutic agent is subject to
enzymatic degradation, enzyme inhibitors can be added to
the composition of SMEDDS. Enzyme inhibitors37 are;
1) Inhibitors that are not based on amino acids. E.g. Paminobenzamidine, FK-448, Cosmostat mesylate, Sodium
glycocolate.
2) Amino acids and modified amino acids e.g.
aminoboronine derivatives and n-acetylcysteine.
3) Peptides and modified peptides e.g. Bacitracin, antipain,
leupeptin, amastatin.
4) Polypeptide protease inhibitors e.g. Apratinin, BowmanBirk inhibitor, Soyabeen trypsin inhibitor, Chicken egg
white trypsin inihibitor.
5) Complexing agent e.g. EDTA, EGTA, 1, 10
Phenanthroline, Hydroxychinoline.
Adsorbants/solidifying agents: This process requires very
high amounts of solidifying aids such as cellulose, lactose
and silicates. Nazzal et al formulated eutectic based solid
self-nanoemulsifying drug delivery systems (SNEDDS)
using interaction between ubiquinone and oils that formed
wax-like paste, which was further mixed with
copolyvidone, maltodextrin and microcrystalline cellulose
to obtain tablets40. Solid self-emulsifying system
comprising goat fat and Tween 65 were formulated for
delivery of diclofenac41. But the goat fat, used as an oil
phase, has very limited solvent capacity and the tablets
were produced using plastic molds without application of
compression force. With lactose and microcrystalline
cellulose as solidifying agents, solid self-microemulsifying
system has been formulated by using an extrusion
spheronization technique. It is reported that transformation
of self-emulsifying system in solid dosage forms by
addition of large amounts of solidifying excipients42. But
in all these studies, to obtain solids with suitable
processing properties, the required ratio of solidifying
excipients to selfemulsifying drug delivery system
(SEDDS) was very high, and it seems to be practically
infeasible for drugs having limited solubility in oil phase.
Gelled selfemulsifying drug delivery system of ketoprofen
has been formulated to serve as an intermediate for further
transformation into semisolid or solid dosage forms43.
Recently liquid self-emulsifying system of loratadine
transformed into solid dosage form by using porous
polystyrene beads as solidifier. But in this study the ratio
of solidifying carrier to self-emulsifying system is low44.
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Table: 2 Example of surfactants, co-surfactant, and co-solvent used in commercial formulations36
Excipient Name (commercial name)
Surfactants/co-surfactants
Polysorbate 20 (Tween 20)
Polysorbate 80 (Tween 80)
Sorbitan monooleate (Span 80)
Polyoxy-35-castor oil(Cremophor RH40)
Polyoxy-40- hydrogenated castor oil (Cremophor RH40)
 Polyoxyethylated glycerides (Labrafil M 2125 Cs)
 Polyoxyethlated oleic glycerides (Labrafil M1944 Cs)
 D-alpha Tocopheryl polyethylene glycol 1000 succinate
(TPGS)






Co-solvents
Ethanol
Glycerin
 Polypylene glycol
 Polyethylene glycol
Lipid ingredients
 Corn oilmono,di,,tri-glycerides

 DL-alpha-Tocopherol
 Fractionated triglyceride of coconut oil (medium-chain
triglyceride)
 Fractionated triglyceride of palm seed oil (medium-chain
triglyceride)
 Mixture of mono-and di-glycerides of caprylic/capric acid
 Medium chain mono-and di-glycerides
 Corn oil
 Olive oil
 Oleic acid
 Sesame oil

 Hydrogenated soyabean oil

 Hydrogenated vegetable oils
Soyabean oil
 Peanut oil
 Beeswax
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Examples of commercial products in which it has been
used
Targretin soft gelatin capsule
Gengraf hard gelatin capsule
Gengraf hard gelatin capsule
Gengraf hard gelatin capsule, Ritonavir soft gelatin capsule
Nerol soft gelatin capsule, Ritonavir oral solution
Sandimmune soft gelatin capsules
Sandimmune oral solution
Agenerage Soft gelatin capsule, Agenarage oral solution
Nerol soft gelatin Capsule, Nerol Oral Solution, Gengraf
hard gelatin Capsule, Sandimmune soft gelatin Capsule,
Sandimmune oral solution
Nerol soft gelatin Capsule, Sandimmune soft gelatin
Capsules
Nerol soft gelatin Capsule, Nerol Oral Solution, Lamprene
soft gelatin capsule, Agenerage Oral solution , Gengraf
hard gelatin capsule
Targretin soft gelatin capsule, Gengraf hard gelatin
capsule, Agenerase soft capsule, Agenerase oral solution
Nerol soft gelatin Capsule, Nerol Oral Solution
Nerol Oral Solution, Fortavase soft gelatin capsule
Rocaltrol soft gelatin capsule, Hectrol soft gelatin capsule
Rocatrol oral solution
Avodat soft gelatin capsule
Fortavase soft gelatin capsule
Sandimmune soft gelatin capsule, Depakene capsule
Sandimmune oral solution
Ritonavir soft gelatin capsule, Norvir soft gelatin capsule
Marinol soft gelatin capsule
Accutane soft gelatin capsule, Vesanoid soft gelatin
capsule
Accutane soft gelatin capsule, Vesanoid soft gelatin
capsule
Accutane soft gelatin capsule
Prometrium soft gelatin capsule
Vesanoid soft gelatin capsule
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Polymers: Inert polymer matrix representing from 5 to
40% of composition relative to the weight, which is not
ionizable at physiological pH and being capable of forming
matrix are used for the formulation of sustained release
SMEDDS38. Ping Gao et al developed new supersaturable
selfemulsifying drug delivery system of paclitaxel by using
hydroxypropylmethyl cellulose (HPMC) polymer as a
precipitation inhibitor with a conventional SEDDS
formulation. In this study it has been observed that the
supersaturated state is prolonged by use of HPMC in the
formulation whereas in the absence of HPMC the SEDDS
formulation undergoes rapid precipitation, yielding a low
paclitaxel solution concentration. The results of
pharamacokinetic study conducted in male Sprague-Dawley
rats shows paclitaxel SEDDS formulation with HPMC
(Supersaturable SEDDS) shows ~10-fold higher maximum
concentration (Cmax) and five-fold higher oral
bioavailability than that of Taxol and SEDDS without
HPMC orally39.
selfemulsification, stability upon dilution and viscosity.
Phase diagrams are useful tools to determine the number
and types of phases, the wt% of each phase and the
composition of each phase at a given temperature and
composition of the system. These diagrams are threedimensional but are illustrated in two-dimensions for ease
of drawing and interpretation.
Other components: Other components might be pH
adjusters, flavors, and antioxidant agents. Indeed a
characteristic of lipid products, particularly those with
unsaturated lipids show peroxide formation with oxidation.
Free radicals such as ROO., RO., and .OH can damage the
drug and induce toxicity. Lipid peroxides may also be
formed due to auto-oxidation, which increases with
unsaturation level of the lipid molecule. Hydrolysis of the
lipid may be accelerated due to the pH of the solution or
from processing energy such as ultrasonic radiation.
Lipophilic antioxidants (e.g. α-tocopherol, propyl gallate,
ascorbyl palmitate or BHT) may therefore be required to
stabilize the oily content of the SMEDDS.
G is the free energy associated with the process (ignoring
FORMULATION OF SMEDDS
The novel synthetic hydrophilic oils and surfactants usually
dissolve hydrophobic drugs to a greater extent than
conventional vegetable oils. The addition of solvents, such
as ethanol, PG and PEG may also contribute to the
improvement of drug solubility in the lipid vehicle45. With a
large variety of liquid or waxy excipients available ranging
from oils through lipids, hydrophobic and hydrophilic
surfactant to water soluble co solvent, there are many
different combinations that could be formulated for
encapsulation in hard or soft gelatin or mixture which
disperse to give fine colloidal emulsions22. The following
should be considered in the formulation of a SMEDDS.

The solubility of the drug in different oil, surfactants
and co solvents

The selection of oil, surfactant and co solvent based on
the solubility of the drug

Preparation of the phase diagram.

The preparation of SMEDDS formulation by
dissolving the drug in a mixture of oil, surfactant and
co solvent46.
Ternary diagram: Pseudo ternary phase diagram is used to
map the optimal composition range for three key excipients
according to the resulting droplet size following
© 2011, JDDT. All Rights Reserved
Mechanism of self-emulsification: Self emulsification
occurs, when the entropy change occurs, dispersion is
greater than the energy required to increase the energy
required to increase the surface area of the dispersion9. The
free energy of conventional emulsion formation is a direct
function of the energy required to create a new surface
between the two phases and can be described by the
equation.
G=Ni ri 2 
Where:
the free energy of mixing),
N is the number of droplets of radius r,
is interfacial energy with time
The two phases of the emulsion will tend to separate, in
order to reduce the interfacial area and subsequently, the
free energy of the system. Therefore, the emulsions
resulting from aqueous dilution are stabilized by
conventional emulsifying agents, which form a monolayer
around the emulsion droplets and hence, reduce the
interfacial energy, as well as providing a barrier to
coalescence47. In case of self-emulsifying system, the free
energy required to form the emulsion is either very low or
positive or negative then, the emulsion process occurs
spontaneously48. Emulsification require very little input
energy, involves destabilization through contraction of local
interfacial regions. For emulsification to occur, it is
necessary for the interfacial structure to have no resistance
to surface shearing30. In earlier work it was suggested that
the case of emulsification could be associated with the ease
by which water penetrates into the various liquid crystal or
phases get formed on the surface of the droplet 7. The
addition of a binary mixture (oil/non-ionic surfactant) to the
water results in the interface formation between the oil and
aqueous continuous phases, followed by the solubilization
of water within the oil phase owing to aqueous penetration
through the interface, which occurs until the solubilization
limit is reached close to the interface8. Further aqueous
penetration will result in the formation of the dispersed
liquid crystalline phase. As the aqueous penetration
proceeds, eventually all materials close to the interface will
be liquid crystal, the actual amount depending on the
surfactant concentration in the binary mixture once formed,
rapid penetration of water into the aqueous cores, aided by
the gentle agitation of the self emulsification process causes
interface disruption and droplet formation. A combination
of particle size analysis and low frequency dielectric
spectroscopy was used to examine self-emulsifying
properties of a series of Imwitor 742 (a mixture of mono-
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Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
and diglycerides of Caprylic acids/Tween 80) systems,
which provided evidence that the formation of the emulsion
may be associated with liquid crystal formation, although
the relationship was clearly complex48. The presence of the
drug may alter the emulsion characteristics, possibly by
interacting with the liquid crystal phase. The droplet
structure can pass from a reversed spherical droplet to a
reversed rod-shaped droplet, hexagonal phase, lamellar
phase, cubic phase or other structures until, after
appropriate dilution, a spherical droplet will be formed
again.
performance, but visual appearance as well. Furthermore,
incompatibilities between the formulation and the gelatin
capsules shell can lead to brittleness or deformation,
delayed disintegration, or incomplete release of drug21.

Heating Cooling Cycle: Six cycles between refrigerator
temperature (4ºC) and 45 ºC with storage at each
temperature of not less than 48 h is studied. Those
formulations, which are stable at these temperatures, are
subjected to centrifugation test.

Centrifugation: Passed formulations are centrifuged
thaw cycles between 21 ºC and +25 ºC with storage at
each temperature for not less than 48 h is done at 3500
rpm for 30 min. Those formulations that does not show
any phase separation are taken for the freeze thaw stress
test.

Freeze Thaw Cycle: Three freeze for the formulations.
Those formulations passed this test showed good
stability with no phase separation, creaming, or
cracking.
CHARACTERIZATION OF SMEDDS
 Particle size: The droplet size of the emulsion is a
crucial factor because it determines the rate and extent of
drug release as well as absorption. Photon correlation
spectroscopy (PCS) is a useful method for determination of
emulsion droplet size especially when the emulsion
properties do not change upon infinite aqueous dilution, a
necessary step in this method50.
 Polarity: Emulsion droplet polarity is also a very
important factor in characterizing emulsification efficiency.
The HLB, chain length, degree of unsaturation of the fatty
acid, molecular weight of the hydrophilic portion and
concentration of the emulsifier have an impact on the
polarity of the oil droplets. Polarity represents the affinity
of the drug compound for oil and/or water and the type of
forces formed. Rapid release of the drug into the aqueous
phase is promoted by polarity50.
 Zeta potential: The charge of the oil droplets in
conventional SMEDDS is negative due to the presence of
free fatty acids; however, incorporation of a cationic lipid,
such as oleylamine at a concentration range of 1.0-3%, will
yield cationic SMEDDS. Thus, such systems have a
positive n-potential value of about 35-45 mV15. This
positive n-potential value is preserved following the
incorporation of the drug compounds.
 Drug precipitation /stability on dilution: The ability
of SMEDDS to maintain the drug in solubilised form is
greatly influenced by the solubility of the drug in oil phase.
If the surfactant or co-surfactant is contributing to the
greater extent in drug solubilisation then there could be a
risk of precipitation, as dilution of SMEDDS will lead to
lowering of solvent capacity of the surfactant or cosurfactant, hence it is very important to determine stability
of the system after dilution. This is usually done by diluting
a single dose of SMEDDS in 250ml of 0.1N HCl solution.
This solution is observed for drug precipitation if any.
Ideally SMEDDS should keep the drug solubilized for four
to six hours assuming the gastric retention time of two
hours.
EVALUATION
Thermodynamic stability studies: The physical stability
of a lipid –based formulation is also crucial to its
performance, which can be adversely affected by
precipitation of the drug in the excipient matrix. In addition,
poor formulation physical stability can lead to phase
separation of the excipient, affecting not only formulation
© 2011, JDDT. All Rights Reserved
105
Dispersibility test: The efficiency is assessed using a
standard USP XXII dissolution apparatus 2. One mL of
each formulation was added to 500 mL of water at 37 ± 0.5
ºC. A standard stainless steel dissolution paddle rotating at
50 rpm provided gentle agitation. The in vitro performance
of the formulations is visually assessed using the following
grading system21:
Grade A: Rapidly forming (within 1 min) nanoemulsion,
having a clear or bluish appearance.
Grade B: Rapidly forming, slightly less clear emulsion,
having a bluish white appearance.
Grade C: Fine milky emulsion that forms within 2 min.
Grade D: Dull, grayish white emulsion having slightly oily
appearance that is slow to emulsify (longer than 2 min).
Grade E: Formulation, exhibiting either poor or minimal
emulsification with large oil globules present on the
surface.
Grade A and Grade B formulation will remain as
nanoemulsion when dispersed in GIT. While formulation
falling in Grade C could be recommend for SEDDS
formulation.
Turbidimetric
Evaluation:
Nepheloturbidimetric
evaluation is done to monitor growth of emulsification.
Fixed quantity of Selfemulsifying system is added to fixed
quantity of suitable medium (0.1N hydrochloric acid) under
continuous stirring (50 rpm) on magnetic plate at ambient
temperature, and the increase in turbidity is measured using
a turbidimeter. However, since the time required for
complete emulsification is too short, it isn’t possible to
monitor the rate of change of turbidity (rate of
emulsification) 48.
Viscosity Determination: The SMEDDS system is
generally administered in soft gelatin or hard gelatin
capsules. So, it can be easily pourable into capsules and
such system should not too thick to create a problem. The
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Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
106
rheological properties of the micro emulsion are evaluated
by Brookfield viscometer43.
the solvent extract was analyzed by suitable analytical
method against the standard solvent solution of drug.
Droplet Size Analysis Particle Size Measurements: The
droplet size of the emulsions is determined by photon
correlation spectroscopy (which analyses the fluctuations in
light scattering due to Brownian motion of the particles)
using a Zetasizer able to measure sizes between 10 and
5000 nm. Light scattering is monitored at 25°C at a 90°
angle, after external standardization with spherical
polystyrene beads43.
Droplet polarity: Droplet polarity and droplet size are
important emulsion characteristics. Polarity of oil droplets
is governed by the HLB value of oil, chain length and
degree of unsaturation of the fatty acids, the molecular
weight of the hydrophilic portion and concentration of the
emulsifier. A combination of small droplets and their
appropriate polarity (lower partition coefficient o/w of the
drug) permit acceptable rate of release of the drug. Polarity
of the oil droplets is also estimated by the oil/water
partition coefficient of the lipophillic drug 9, 38.
Refractive Index and Percent Transmittance: Refractive
index and percent transmittance proved the transparency of
formulation. The refractive index of the system is measured
by refractometer by placing drop of solution on slide and it
compare with water (Refractive index of water1.333). The
percent transmittance of the system is measured at
particular wavelength using UV-spectrophotometer keeping
distilled water as blank. If refractive index of system is
similar to the refractive index of water and formulation
have percent transmittance > 99 %, then formulation has
transparent nature.
Electro conductivity Study: The SEDD system contains
ionic or non-ionic surfactant, oil, and water. So, this test is
used to measure the electroconductive nature of system.
The electro conductivity of resultant system is measured by
electroconductometer.
In vitro Diffusion Study: In vitro diffusion studies are
performed to study the release behavior of formulation
from liquid crystalline phase around the droplet using
dialysis technique43.
Sustained release: For this, dissolution study is carried out
for SMEDDS. Drugs known to be insoluble at acidic pH
can be made fully available when it is incorporated in
SMEDDS38.
Yield of the smedds: The SMEDDS formed is filtered
from the solvent, dried in the desiccators and weighed to
get the yield of the SMEDDS formulated per batch.
Percentage yield can be calculated by formula48
% recovery = W1 / W2 + W3 * 100
(1)
Where, W1 is the weight of the SMEDDS formulated.
W2 weight of the drug added.
W3 is the weight of the lipid and surfactant used
as the starting material.
The bioavailability of some of the poorly soluble drugs is
enhanced by SMEEDS enlisted in Table 3 and examples of
marketed SEDDS formulations are enlisted in Table 4.
Drug content: Drug from pre-weighed SMEDDS is
extracted by dissolving in suitable solvent. Drug content in
Table: 3 Example of bioavailability enhancement of pooly soluble drug after administration of SMEDDS formulations51
COMPOUND
Win 54954
Cyclosporin
Halofantrine
Ontazolast
Simvastatin
Danazol
Carvediol Solvent green 3
Silymarin
Atorvastatin
Itraconazole
Atovaquone
Seocalcitol
© 2011, JDDT. All Rights Reserved
OBSERVATIONN AFTER STUDY
No difference in BA but improved reproducibility, increased C max
Increased BA and C max and reduced T max from SMEDDS
Increased Cmax, AUC and dose linearity and reduced food effect from SMEDDS
Reduced intra- and inter-subject variability from SMEDDS
Trend to higher BA from LCT SMEDDS
BA increase of at least 10- fold from all lipid based formulations
BA 1.5 fold higher from SMEDDS
BA from LCT solution and LC-SMEDDS 7- fold and 6- fold higher than that from
MC-SMEDDS
BA 1.7-fold higher from SMEDDS
BA approximately 2-and 50- fold higher from SMEDDS
BA significantly increased from all SMEDDS
Increased BA and reduced food effect
BA 3-fold higher from SMEDDS
BA LC-SMEDDS=MC-SMEDDS
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Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
107
Table 4: Examples of marketed SEDDS formulations52
DRUG NAME
Neoral®
COMPOUND
Cyclosporine A/I
DOSAGE FORM
Soft gelatin capsule
COMPANY
Novartis
INDICATION
Immune suppressant
Norvir
Ritonavir®
Soft gelatin capsule
Abbott Laboratories
HIV antiviral
Fortovase®
Agenerase®
Saquinavir
Amprenavir
Soft gelatin capsule
Soft gelatin capsule
Hoffmann-La Roche inc.
Glaxo Smithkline
HIV antiviral
HIV antiviral
Targretin®
Rocaltrol®
Convulex®
Lipirex®
Sandimmune®
Gengraf®
Bexarotene
Calcitriol
Valproic acid
Fenofibrate
Cyclosporine A/II
Cyclosporine A/III
Soft gelatin capsule
Soft gelatin capsule
Soft gelatin capsule
Hard gelatin Capsule
Soft gelatin capsule
Hard gelatin Capsule
Ligand
Roche
Pharmacia
Genus
Novartis
Abbott Laboratories
Antineoplastic
Calcium Regulator
Antiepileptic
Antihyperlipoproteinemic
Immuno Suppressant
Immuno Suppressant
FACTORS AFFECTING SMEDDS
Drug dose: Drugs, which are administered at very high
dose, are not suitable for SMEDDS, unless they exhibit
extremely good solubility in at least one of the components
of SMEDDS, preferably lipophilic phase. The drugs exhibit
limited solubility in water and lipids (typically log P values
of approximately 2) are most difficult to deliver by
SMEDDS.
Drug solubility in oil phase: The ability of SMEDDS to
maintain the drug in solubilised form is generally
influenced by the solubility of the drug in oily phase. If the
surfactant or co-surfactant is contributing to a greater extent
of drug solubilization, then there could be a risk of
precipitation, as dilution of SMEDDS will lead to lowering
of solvent capacity of surfactant or co surfactant.
Equilibrium solubility measurement: It can be carried out
to anticipate potential cases of precipitation in the gut.
However, crystallization could be slow in solubilizing
environment of the gut. Poutons study reveals that such
formulation can take up to 5 days to reach equilibrium and
that the drug can remain in a super saturated state up to 24
hours after the initial emulsification event9.
Polarity of lipid phase: The polarity of lipid phase is one
of the factors that govern the release from the
microemulsion. HLB, chain length and degree of
unsaturation of fatty acid, molecular weight of the
lipophilic portion and concentration of the emulsifier
govern the polarity of droplets. In fact the polarity reflects
the affinity of the drug for oil and /or water and the type of
forces involved. The high polarity will promote rapid rate
of release of the drug into the aqueous phase. This is
conformed by the observation of Sang-Cheol et al. who
observed that the rate of release of Idebenone from
SMEDDS is dependent upon the polarity of oil phase used.
The highest release was obtained with the formulation that
had oily phase with highest polarity53.
Charge of emulsion droplets: Multiple physiological
studies have proved that the apical potential of absorptive
cells, as well as that of all other cells in the body, is
negatively charged with respect to the mucosal solution in
the lumen54. Gershanik and Benita have shown that
positively charged emulsion droplets formed by adding
oleylamine (OA) to appropriate SEDDS undergo
electrostatic interaction with the CACO-2 monolayer and
the mucosal surface of the everted rat intestine55. This
formulation enhanced the oral bioavailability of
progesterone in young rats. Benzoic acid had a dual
function on the SEDDS; it could improve the selfemulsifying performance of self-emulsifying oily
formulations (SEOFs) and self-microemulsifying oily
formulations (SMEOFs) in 0.1N HCl due to formation of a
positively charged emulsion56. SMEDDS designed for the
oral delivery of lipophilic drugs are enlisted in Table 5.
Table 5: Examples of smedds designed for the oral delivery of lipophilic drugs57
Delivery system
Oil
Surfactant
%w/w
Solvent
Drug compound
SMEDDS
-
96
-
Indomethacin
SMEDDS (sandimmun
neoral)
Smedds
(sandimmun neoral)
SMEDDS
Hydrolysed
Corn oil
Hydrolysed
Corn oil
Triglyceride maisine 351, cremophore EL 58
ethanol halofantrine
5(lll,lml, Mlm)
Glyceryl dioleate
Dl-alpha tocopherol
Polyglycolized glycerides
(hlb:1-14)
Polyglycolized
glycerides,
POE-castor oil derivative
Polyglycolized glycerides,
POE-castor oil derivative
Maisine 35-1, cremophor EL
Drug
content
4
Na
Glycerol
Csa
10
Na
Ethanol
CsA
10
58
Ethanol
Halofantrine
5
Cremophor EL, PEG400
55-58
62
Ethanol
Ethanol
Paclitaxel(±CsA)
Paclitaxel
5.7-6.25
3
SMEDDS
SMEDDS
© 2011, JDDT. All Rights Reserved
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CODEN (USA): JDDTAO
Parul et al
Journal of Drug Delivery & Therapeutics; 2013, 3(1), 98-109
CONCLUSION
Self-microemulsifying drug delivery systems are a
promising approach for the formulation of drug compounds
with poor aqueous solubility. The oral delivery of
hydrophobic drugs can be made possible by SMEDDSs,
108
which have been shown to substantially improve oral
bioavailability and thus the dose of the drug can be reduced.
With future development of this technology, SMEDDSs will
continue to enable novel applications in drug delivery and
solve problems associated with the delivery of poorly
soluble
drugs.
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